Renal cell carcinomas (RCC) are a frequent genitourinary malignancy with a morphological characteristic of an irregular nuclear shape, which is used as the index of RCC grading. In addition, p53 inactivation without genetic mutation and radiation-resistance are also suggested as the hallmark of RCC. In contrast, pVHL (Hippel-Lindau tumor suppressor protein) is frequently mutated from the early stage of RCC. However, molecular mechanisms have not yet been elucidated for a pleomorphic nucleus, p53 inactivation and radiation resistance.
Cancer is well defined as an aging related disease and also as a genetic disease. It has been clearly demonstrated why aged populations shows higher susceptibility to cancer. In general, it has been explained by multistep carcinogenesis. To reach malignant cancer, normal cells should accumulate significant genetic mutation. Thus, cancer formation requires a long period for development. However, in the case of the familial cancer syndromes including Li-fraumeni syndrome, von Hippel Lindau, and familial adenomatosis colis, the tumor formation thereof does not takes much time, and even rapidly progresses under a certain condition. In this regard, a recent, very interesting report has claimed that the biological function of the strong tumor suppressor p53 is declined in the aging process. Since p53 is a gatekeeper tumor suppressor, its functional decline may promote cancer development. Thus aging related change of the cellular context or gene expression profiling which can suppress the p53 function would be an important clue to understanding carcinogenesis in aged populations.
RCC is well known as an age related cancer. Its onset, although not high in young populations, is obviously increased in the aging process. In addition, RCC shows nuclear irregularity and resistance to IR treatment. However, the genetic mutation of p53, which has been suggested as the cause of IR-resistance, is very low. These features indicate that there might be a novel mechanism that can suppress the p53 function in RCC.
An additional significant genetic event of RCC is frequent mutation of pVHL. Although pVHL has been cloned from the human cancer syndrome von Hippel Lindau, its genetic mutation is known to reach 70% in primary clear cell renal carcinoma. As an E3 ligase, pVHL serves to degrade HIF-1a and block transcriptional activity. Since HIF-1a induces VEGF, EPO, and other pro-angiogentic factors in response to hypoxia, the activation of HIF-1a seems to be important for cancer progression, in particular, tumor-angiogenesis progression. However, in many kinds of solid cancers, HIF-1a can be stabilized and activated as a hypoxic condition is established at the inner cell mass of a tumor. In contrast, the deletion or functional loss of pVHL seems to be inessential for earlier carcinoma development. Moreover, angiogenesis is required at a late stage of cancer and the kidney is histologically characterized by plenty of well organized blood vessels. Hence, pVHL loss for achieving angiogenesis in the early stage of RCC is not critical for tumor formation. In fact, pVHL deletion is not detected in other kinds of invasive cancers. Thus, these features suggest that a novel tumor suppressing role of pVHL would exist and should be related with an RCC-specific function.
Taking into full consideration the fact that the onset of RCC dramatically increases in the aging process, the p53 function declines even without a genetic mutation, and pVHL is frequently mutated at an early stage, the present inventors proposed the hypothesis that the loss of pVHL would be related with aging-related gene expression, which can suppress the p53 function. To explore the hypothesis, a focus was made on the nuclear irregularity of RCC, which resembles the nuclear deformation in Hutchinson-Gilford progeroid syndrome (HGPS), discovering that progerin, a causal gene of HGPS, is expressed in aged cells.
In this context, the present inventors made an examination of relationship between the characteristics of RCC and the elevated expression of progerin, and found that the elimination of progerin can ameliorate the nuclear irregularity of RCC and restore p53 responsibility to DNA damage, and that both the elevated expression of progerin and the inactivation of p53 are attributable to pVHL dysfunction. In addition, pVHL can interact with progerin and block the progerin-induced p14/ARF inactivation whereas progerin sequesters p14, resulting in the inactivation of p53 and nuclear irregularity. It was also found that progerin expression can be detected in human leukemia samples and derived primary cell lines. From these data, progerin expression was discovered to be important for cancer progression, in particular, in an aged population, which leads to the present invention.
Expression of progerin can induce several morphological changes such as nuclear irregularity and a reduction of nuclear-plasmic Lamin A (LMN A). In fact, reduction or knock down of Prg can rescue the nuclear deformation, indicating that gained function of progerin is a causal factor for HGPS. In addition, it has been reported that progerin is accumulated in aged normal fibroblasts and evokes nuclear deformation. In iPSC (induced pluripotent stem cells) of HGPS patient, Prg as well as LMN A/C expression are obviously reduced and cellular senescence markers including nuclear deformation, H3K9me3, and SA-β-gal, are restored. In contrast, differentiated HGPS cells re-express the senescence markers, following progerin expression.
Since aging phenotypes and progression of HGPS seem to resemble normal aging or senescence processes, the present inventors investigated the function of progerin in cellular senescence through a study on HGPS, and found that a senescence progress proceeds with the interaction of progerin with Lamin A. Inhibitors against the interaction were excavated by chemical screening and evidenced to exert therapeutic effects on aging-related diseases, leading to the present invention.